Derivatives of 5-pentylamino-5-oxopentanoic and 4-pentylamino-4-oxobutanoic acids with antagonistic activity towards cholecystokinin

ABSTRACT

New original derivatives are described of 5-pentylamino-5-oxopentanoic and 4-pentylamino-4-oxobutanoic acids having the formula: ##STR1## in which n is 1 or 2, R 1  is selected from the groups 2-naphthyl, 2 (or 3)-quinolinyl, 2 (or 3)-indolyl, 2 (or 3)-benzofuranyl, 2 (or 3)-benzothiophenyl, and R 2  is a pentyl group or an alkoxyalkyl group with 4 or 5 carbon atoms, preferably pentyl, 2-ethoxyethyl, 3-methoxypropyl or 3-ethoxypropyl. 
     The compounds have a powerful antagonistic activity towards cholecystokinin and are particularly useful in the treatment of illnesses of the digestive system, such as colitis, biliary diskinesia, pancreatitis or in the treatment of disorders of the central nervous system imputable to deficiencies in the physiological neuron levels of cholecystokinin or other related bioactive polypeptides.

This is a division of application Ser. No. 07/133,844 filed Dec. 16,1987 which is now U.S. Pat. No. 4,826,878.

The subjects of the present invention are original derivatives of5-pentylamino-5-oxopentanoic acid and 4-pentylamino-4-oxobutanoic acidwhich may be represented by the general formula shown below ##STR2## inwhich n is 1 or 2, R₁ is selected from the groups 2-naphthyl, 2 (or3)-quinolinyl, 2 (or 3)-indolyl, 2 (or 3)-benzofuranyl, 2 (or3)-benzothiophenyl, and R₂ is a pentyl group or an alkoxyalkyl groupwith 4 or 5 carbon atoms.

R₂ is preferably selected from the group consisting of pentyl,2-ethoxyethyl, 3-methoxypropyl and 3-ethoxypropyl.

The compounds which are the subject of the present invention showinteresting pharmacological properties in mammals, which properties maybe attributed to the powerful antagonistic activity towardscholecystokinin (CCK) or other bioregulatory peptides displayed by manyof the subject compounds.

The compounds according to the invention may therefore be used toadvantage in the treatment of various illnesses in man, such asillnesses of the digestive system, for example in the treatment ofcolitis, biliary diskinesia and pancreatitis.

On the basis of their pharmacological characteristics, their use mayalso be envisaged in the treatment of mental disorders imputable todeficiencies in the physiological neuron levels of CCK or otherbioactive polypeptides and even in the treatment of anorexia.

The compounds which are the subject of the invention, as mentionedabove, have a powerful anti-CCK activity in various experimentalsituations both in vivo and in vitro.

Thus, in nanomolar concentrations they inhibit the binding of markedcholecystokinin to the cell membranes of ox gall-bladder, a tissue whichis considered to be a target organ for the physiological action ofcholecystokinin.

These compounds are, moreover, also very active in vivo. For example,they inhibit, in a dose-dependent manner, some even at doses lower than1 mg/kg, the contraction and emptying of the gall-bladder induced by eggyolk which is an inducer for the endogenous release of CCK. They alsoencourage emptying of the stomach as they inhibit the pyloriccontraction caused by CCK. Their protective action is, moreover,particularly powerful in experimental pancreatitis, for example inpancreatitis induced by sodium taurocholate.

Pharmaceutical forms of the compounds which are the subject of theinvention may be prepared by conventional techniques, for example, aspills, capsules, suspensions, solutions and suppositories and may beadministered orally, parentally or rectally.

The active ingredient is typically administered to the patient in aratio of from 0.01 to 5 mg/kg of body weight per dose. For parenteraladministration it is preferable to use a water-soluble salt of thesubject compounds, such as the sodium salt or another salt which isnon-toxic and pharmaceutically acceptable. As inactive ingredients,substances commonly used in the pharmaceutical industry may be used,such as excipients, binders, flavourings, dispersants, colourings,humectants, etc.

The method for the preparation of derivatives of5-pentylamino-5-oxopentanoic acid and 4-pentylamino-4-oxobutanoic acidaccording to the invention is characterised in that it includes thesteps of:

(a) reacting an internal anhydride of the formula: ##STR3## in which nand R₁ have the meanings attributed to them above, with an amine offormula ##STR4## in which R₂ has the meaning attributed to it above, ina molar ratio of from 1 to 5 at a temperature of from -10° C. to 10° C.and recovering the compounds of formula (I) from the reaction mass.

The internal anhydrides of formula II are new compounds which have notbeen synthesised before.

These internal anhydrides (II) are obtained by the steps of:

(b) reacting glutamic acid under Schotten-Bauman conditions with anequimolar quantity of an acyl chloride of formula R₁ --CO--Cl in whichR₁ and n have the meanings attributed to them above, at a temperature offrom 0° to 15° C. to obtain the N-acylated compound of formula: ##STR5##

(c) dehydrating the compound of formula (III) by reaction in thepresence of acetic anhydride in a molar ratio of from 1 to 10, alone orin the presence of an inert solvent miscible therewith, at a temperatureof from 20° C. to the reflux temperature.

The series of steps constituting the method of the invention is shown asa whole in the following reaction scheme: ##STR6##

The acylation step b is carried out at a temperature of approximately 5°C. over a period of from 1 to 24 hours, preferably 12 hours.

In step c, the reaction time is typically approximately 30 minutes to 12hours, preferably approximately 3 hours and the quantity of aceticanhydride is preferably 3 moles per mole of compound (III).

In the amidation step "a", the amine of formula ##STR7## is preferablyintroduced in a molar ratio of 2.5 to 1 relative to the internalanhydride (II) and the reaction is carried out over a period ofapproximately 30 minutes to 12 hours, preferably 3 hours.

The following examples are given in order better to illustrate theinvention.

EXAMPLE 1 Preparation of 2-naphthoyl-glutamic acid (compound 1 of table1)

100 ml of 1N sodium carbonate and 19.1 g (0.1 moles) of 2-naphthoylchloride are added simultaneously with agitation and cooling to asolution containing 14.7 g (0.1 moles) of L-glutamic acid in 200 ml of1N sodium carbonate cooled to 5° C. over a period of approximately 30minutes.

The mixture is left to react for 12 hours. It is made acid to Congo redwith concentrated HCl and the precipitate thus formed is filtered out.The precipitate is crystallised from H₂ O-ethanol (2/1).

M.P.: 159°-61° C. TLC (isoamyl alcohol-acetone-H₂ O: 5/2/2): Rf 0.27.26.5 g obtained. Yield 92%.

All the compounds of formula III are synthesised by the same method (seescheme above).

The compounds thus obtained are given in Table 1 below together withsome of their identifying characteristics, the yields obtained and thecrystallisation solvents used.

                  TABLE 1                                                         ______________________________________                                        Nacyl-glutamic and aspartic derivatives having the formula                     ##STR8##                                                                                                      Solvents of                                  Com-                     Melting crystal-                                                                              %                                    pounds                                                                              n     R.sub.1      point (°C.)                                                                    lisation                                                                              Yield                                ______________________________________                                        1     2     2-naphthyl   166-68  Water-  92.0                                                                  ethanol 2:1                                  2     2     2-indolyl    142-44  Water-  72.5                                                                  ethanol 3:1                                  3     2     3-indolyl    150-54  Water-  73.0                                                                  ethanol 3:1                                  4     2     2-quinolinyl  98-104 Ethyl   55.0                                                                  acetate-                                                                      ligroin                                      5     2     2-benzofuranyl                                                                             149-52  Water   73.1                                 6     2     3-benzofuranyl                                                                             160-63  Water   78.0                                 7     2     2-benzothiophenyl                                                                          158-61  Water   77.5                                 8     1     2-naphthyl   174-76  Water-  90.5                                                                  ethanol 3:1                                  9     1     2-indolyl    147-50  Water-                                                                        ethanol 3:1                                                                           74.5                                 ______________________________________                                    

EXAMPLE 2 Preparation of 2-naphthoyl-glutamic anhydride (compound 10 ofTable 2)

30.6 g (0.3 moles) of acetic anhydride with 60 ml of isopropyl ether areadded to 30.1 g (0.1 moles) of 2-naphthoyl glutamic acid. The mixture isheated under reflux (73°-77° C.) for 2 hours. It is cooled, filtered,washed with a little ether to remove residual acetic anhydride anddried. 24.8 g are thus obtained. Yield 88%.

M.P.: 181°-82° C.

All the compounds of formula II are synthesised by the same method (seescheme). Numerous examples of these compounds with some of theiridentifying characteristics, as well as the yields obtained, are givenby way of example in Table 2 below.

                  TABLE 2                                                         ______________________________________                                        Derivatives of Nacyl-glutamic and aspartic anhydride                          having the formula                                                             ##STR9##                                                                                                  Melting                                          Compounds                                                                             n      R.sub.1       point (°C.)                                                                     % Yield                                 ______________________________________                                        10             2-naphthyl    181-82   88                                      11      2      2-indolyl     194-96   86                                      12      2      3-indolyl     197-99   83                                      13      2      2-quinolinyl  150-52   68                                      14      2      2-benzofuranyl                                                                              176-78   84                                      15      2      3-benzofuranyl                                                                              183-85   81                                      16      2      2-benzothiophenyl                                                                           177-80   93                                      17      1      2-naphthyl    201-03   90                                      18      1      2-indolyl     195-97   85                                      ______________________________________                                    

EXAMPLE 3 Preparation ofD,L-4-(2-naphthoylamino)-5-(di-n-pentylamino)-5-oxopentanoic acid(compound 19 of Table 3)

28.3 g (0.1 moles) of 2-naphthoyl-glutamic anhydride are placed in areactor and suspended in 100 ml. of water. The suspension is cooled toapproximately 5° and 39.3 g (0.25 moles) of di-n-pentylamine are addeddropwise over a period of approximately 15 minutes. The mixture is leftto react for 3 hours at this temperature and acidified with glacialacetic acid. It is filtered, washed with water until neutral and dried.25.8 g are thus obtained. Yield 58.5%.

M.P. 119°-20° C. (crystallised from ethyl acetate). TLC: Rf 0.95(isoamyl alcohol-acetone-H₂ O: 5/2/2).

All the compounds of formula I (see scheme) are synthesised by the samemethod.

Numerous examples of these compounds together with some of theiridentifying characteristics and the yields obtained are given in thetable below.

                                      TABLE 3                                     __________________________________________________________________________    Derivatives having the formula                                                 ##STR10##                                                                    Com-                    Melting                                                                             Solvents of Yield                               pounds                                                                            n R.sub.1  R.sub.2  point (°C.)                                                                  Crystallisation                                                                        Rf*                                                                              (%) FORMULA                         __________________________________________________________________________    19  2 2-naphthyl                                                                             pentyl   119-20                                                                              Ethyl acetate                                                                          0.95                                                                             58.5                                                                              C.sub.26 H.sub.36 N.sub.2                                                     O.sub.4                         20  2 2-indolyl                                                                              pentyl   190-92                                                                              Ethyl acetate                                                                          0.95                                                                             54.0                                                                              C.sub.24 H.sub.35 N.sub.3                                                     O.sub.4                         21  2 3-indolyl                                                                              pentyl   197-99                                                                              Ethyl acetate                                                                          0.92                                                                             47.0                                                                              C.sub.24 H.sub.35 N.sub.3                                                     O.sub.4                         22  2 2-quinolinyl                                                                           pentyl   81-4  Iso-propyl ether                                                                       0.89                                                                             24.0                                                                              C.sub.25 H.sub.35 N.sub.3                                                     O.sub.4                         23  2 2-benzofuranyl                                                                         pentyl   117-18                                                                              Ethyl acetate                                                                          0.88                                                                             52.5                                                                              C.sub.24 H.sub.34 N.sub.2                                                     O.sub.5                         24  2 3-benzofuranyl                                                                         pentyl    110-113                                                                            Ethyl acetate                                                                          0.85                                                                             51.0                                                                              C.sub.24 H.sub.34 N.sub.2                                                     O.sub.5                         25  2 2-benzothiophenyl                                                                      pentyl   123-25                                                                              Iso-propyl ether                                                                       0.90                                                                             59.0                                                                              C.sub.24 H.sub.34 N.sub.2                                                     O.sub.4 S                       26  1 2-naphthyl                                                                             pentyl   133-35                                                                              Ethyl acetate                                                                          0.71                                                                             63.0                                                                              C.sub.25 H.sub.34 N.sub.2                                                     O.sub.4                         27  1 2-indolyl                                                                              pentyl   195-98                                                                              Ethyl acetate                                                                          0.73                                                                             51.5                                                                              C.sub.23 H.sub.33 N.sub.3                                                     O.sub.4                         28  2 2-naphthyl                                                                             3-methoxypropyl                                                                         98-100                                                                             Iso-propyl alcohol                                                                     0.80                                                                             56.5                                                                              C.sub.25 H.sub.34 N.sub.2                                                     O.sub.5                         29  2 2-naphthyl                                                                             2-ethoxyethyl                                                                          110-12                                                                              Iso-propyl alcohol                                                                     0.82                                                                             44.0                                                                              C.sub.25 H.sub.34 N.sub.2                                                     O.sub.5                         30  2 2-naphthyl                                                                             3-ethoxypropyl                                                                         94-6  Iso-propyl alcohol                                                                     0.84                                                                             39.0                                                                              C.sub.26 H.sub.36 N.sub.2                                                     O.sub.5                         31  2 2-indolyl                                                                              3-methoxypropyl                                                                        167-70                                                                              Iso-propyl alcohol                                                                     0.83                                                                             52.0                                                                              C.sub.23 H.sub.33 N.sub.3                                                     O.sub.5                         32  2 2-benzofuranyl                                                                         3-methoxypropyl                                                                        85-7  Iso-propyl ether                                                                       0.79                                                                             44.5                                                                              C.sub.23 H.sub.32 N.sub.2                                                     O.sub.6                         33  1 2-naphthyl                                                                             3-methoxypropyl                                                                        106-09                                                                              Iso-propyl alcohol                                                                     0.68                                                                             56.0                                                                              C.sub.24 H.sub.32 N.sub.2                                                     O.sub.5                         __________________________________________________________________________     *The values shown in the table relate to the eluent: isoamyl                  alcoholacetone-water: 5/2/2                                              

The powerful anti-cholecystokinin (anti-CCK) activity of the compoundsof the invention will now be documented by a series of pharmacologicalexperiments conducted both in vitro and in vivo.

Studies on binding to the cell membrane of ox gallbladders

The capacity of some compounds of the invention to inhibit the bindingof (125-I)-Bolton Hunter-CCK-8 to the cholecystokinin receptors of oxgallbladder membranes was evaluated by comparison with the displacementinduced by cold (unmarked) CCK.

The ox gallbladder cell membranes were prepared by homogenisation withTris buffer (pH 7.4) and centrifuging of the homogenate at 50,000gravity for 10 minutes. The membranes were then incubated together withthe radioactive tracer and the compounds under study for 2 h at 25° C.

After the supernatant liquid had been discarded, the radioactivityassociated with the pellet was determined with a liquid scintillator.The specific binding was determined as the difference between thebinding in the absence and in the presence of 10⁻⁶ M CCK-8.

The results obtained are given in Table 4 which shows the IC50 values,that is the concentration (in moles/liter) of the antagonist which isable to displace 50% of the (125-I)-CCK-8 from the receptors.

    ______________________________________                                                  IC50 (moles/            IC50 (moles/                                Compounds liter)     Compounds    liter)                                      ______________________________________                                        CCK-8     0.2 × 10.sup.-9                                                                    Compound 26  6.6 × 10.sup.-9                       Compound 19                                                                             2.2 × 10.sup.-9                                                                    Compound 27  2.4 × 10.sup.-8                       Compound 20                                                                             2.1 × 10.sup.-8                                                                    Compound 28  5.6 × 10.sup.-9                       Compound 21                                                                             7.8 × 10.sup.-8                                                                    Compound 29  9.2 × 10.sup.-9                       Compound 22                                                                             1.2 × 10.sup.-7                                                                    Compound 30  0.7 × 10.sup.-8                       Compound 23                                                                             1.2 × 10.sup.-8                                                                    Compound 31  8.6 × 10.sup.-8                       Compound 24                                                                             7.5 × 10.sup.-8                                                                    Compound 32  4.0 × 10.sup.-8                       Compound 25                                                                             9.0 × 10.sup.-8                                                                    Compound 33  8.6 × 10.sup.-9                       ______________________________________                                    

From the data given in the table it can be seen that the claimedcompounds antagonise the binding of CCK by 50% at concentrations which,for the most active compounds, are only 10-20 times greater than that ofthe specific antagonist, thus demonstrating a very high specificity ofaction.

In order to confirm the results of this study in vitro, some of the moreactive compounds were also tested in vivo.

Antispastic activity on the gallbladder in mice

Emptying of the gall bladder was induced by a single oral administrationof 1 ml of a 30% suspension (weight/volume) of lyophylised egg yolk in aphysiological solution.

As stated above once it has been absorbed egg yoke induces a release ofendogenous CCK. This dose was selected as it causes practically completeemptying of the gallbladder.

The antagonistic compounds were administered intraperitoneally (i.p.) 15minutes before the contractant.

The % antispastic activity for each dose was calculated from thefollowing formula: ##EQU1## where P₁ =the average weight of thegallbladders of the group of animals treated with the drug plus thecontractant.

P₂ =the average weight of the gallbladders of the group of animalstreated with the contractant only.

P₃ --the average weight of the gallbladders of the control group ofanimals.

The compounds were tested at various doses so as to enable thecalculation of an ID50 value, that is the dose (in mg/kg i.p.) which isable to inhibit the contractant effect of the egg yolk by 50%.

The results obtained are given in Table 5 where the effects obtained areexpressed as the ID50.

                  TABLE 5                                                         ______________________________________                                        antispastic activity on contraction of the                                    gallbladder induced by egg yolk.                                                                    % inhibition of                                                    Doses      the emptying of                                                                           ID50 (1)                                    Compound   (mg/kg i.p.)                                                                             the gallbladder                                                                           (mg/kg i.p.)                                ______________________________________                                        19         0.03       12.1                                                               0.1        41.2        0.11                                                   0.3        83.7        (0.99)                                      26         0.1        17.0                                                               0.3        30.8        0.53                                                   1.0        66.7        (0.97)                                      28         0.1        16.5                                                               0.3        36.2        0.62                                                   1.0        58.8        (0.99)                                      ATROPINE   5           3.7                                                               10         21.6        INACTIVE                                               15         10.5                                                    PAPAVERINE 25         0                                                                  50         0           INACTIVE                                               75         26.1                                                    ______________________________________                                         (1): r = the coefficient of correlation of the straight line of               regression.                                                              

The emptying of the gallbladder is reduced by the compounds of theinvention in a dose-dependent manner.

At a dose of 0.3 mg/kg the compound 19 almost completely blocks thecontraction induced by the egg yolk.

Atropine, on the other hand, is inactive and papaverine is slightlyactive but only at the toxic dose of 75 mg/kg which causes the death of20% of the animals treated.

Antispastic activity on pyloric contraction in rats

This experiment shows the contractant effect of CCK on the pyloricsphincter. A dose of 8 mcg/kg i.p. of CCK was used, which induced asub-maximal contraction of the pylorus. The antagonistic compounds wereadministered (i.p.) 15 minutes before the contractant. 10 minutes afteradministration of the contractant, the animals were treated per os with25 ml/kg of H₂ O. 5 minutes after the administration the animals werekilled, their stomachs removed and the gastric content measured byremoval with a syringe.

The % antispastic activity for each dose administered was calculatedfrom the following formula: ##EQU2## where V₁ =the volume of gastriccontent of the group of animals treated with the drug plus thecontractant.

V₂ =the volume of gastric content of the group of animals treated withthe contractant only.

V₃ =the volume of gastric content of the control group of animals.

Various doses of the compounds were tested so as to enable thecalculation of an ID50 value, that is the dose (in mg/kg i.p.) which isable to inhibit the contractant effect of CCK by 50%.

The results obtained are given in Table 6 where the effects obtained areexpressed as the ID50.

                  TABLE 6                                                         ______________________________________                                        Antispastic activity on the pyloric                                           contraction induced by CCK in rats.                                                               % inhibition of                                                    Doses      the pyloric   ID50 (1)                                    Compound (mg/kg i.p.)                                                                             contraction   (mg/kg i.p.)                                ______________________________________                                        19        0.01      17.3                                                                0.03      28.7          0.05                                                 0.1        70.7                                                               0.3        95.5          (0.98)                                      26        0.03      24.8                                                               0.1        50.0          0.14                                                 0.3        57.7                                                               1.0        78.9          (0.98)                                      28        0.03      12.5                                                               0.1        29.2          0.30                                                 0.3        46.7                                                               1.0        73.0          (0.99)                                      ______________________________________                                         (1): in brackets r = coefficient of correlation of the straight line of       regression.                                                              

The pyloric contraction caused by 8 mcg/kg of CCK-8 is 50% inhibited bysome of the compounds of the invention at very low doses of between 50and 300 mcg/kg, that is at doses only 6-37 times greater than that ofthe hormonal contractant.

Pancreatitis induced by sodium taurocholate

The method described by Aho et al. (Scandinavian J. Gastroenterology 15(1980), 411-16) was followed.

Male rats weighing approximately 250 g were subjected to laparotomy andthe pancreas exposed. 0.3 ml of a 6% solution of sodium taurocholatewere injected directly into the pancreatic tissue.

The products under examination were administered intraperitoneally(i.p.) 30 minutes before the operation and 3 hours after the operation.

6 hours after the laparotomy, blood was taken from the retro-orbitalplexus after anaesthesia with ether, the animals were killed and thepancreas was removed and weighed. The activity of the serum amylase wasdetermined by the Ceska method (Clin. Chim. Acta 26 (1969), 437-444).

The compounds were tested at various doses so as to enable thecalculation of an ID50 value, that is the dose (in mg/kg i.p.) which isable to inhibit the toxic effect of the sodium taurocholate by 50%,expressed both as a % inhibition of the increase in weight of thepancreas and as a % inhibition of the increase in serum amylase.

The results obtained with the compounds 19 and 28 are given in Table 7.

                                      TABLE 7                                     __________________________________________________________________________    Examples of protective activity of the claimed compounds in experimental      pancreatitis induced by taurocholate in rats.                                                % RATIO     % INHIBITION AMYLASE IN                                                                             % INHIBITION                                PANCREAS WEIGHT                                                                           WEIGHT INCREASE                                                                            THE SERUM                                                                              AMYLASE INCREASE                            ANIMAL WEIGHT                                                                             (ID50 mg/k g ip)                                                                           (U/ml)   (ID50 mg/kg                  __________________________________________________________________________                                                     ip)                          Controls       0.39        --           8.0      --                           Controls + taurocholate                                                                      0.54        --           16.6     --                           Compound 19 (1 mg/kg) +                                                       taurocholate   0.49        33.3         12.7     45.3                         Compound 19 (3 mg/kg) +                                                       taurocholate   0.43        73.3         10.0     76.7                         Compound 19 (10 mg/kg) +                                                      taurocholate   0.40        93.3         8.8      90.7                                        ID50 = 1.7  (r = 0.98)   ID50 = 1.1                                                                             (r = 0.98)                   Controls       0.35        --           7.7      --                           Controls + taurocholate                                                                      0.59        --           13.7     --                           Compound 28 (3 mg/kg) +                                                       taurocholate   0.52        29.2         11.0     45.0                         Compound 28 (10 mg/kg) +                                                      taurocholate   0.47        50.0         9.6      68.3                         Compound 28 (20 mg/kg) +                                                      taurocholate   0.43        66.6         8.4      88.3                                        ID50 = 9.2  (r = 0.99)   ID50 = 4.1                                                                             (r = 0.99)                   __________________________________________________________________________     (r) = coefficient of correlation                                         

Sodium taurocholate induces pancreatitis which causes an increase inweight of the organ, which also becomes oedematous, lacking inelasticity and haemorrhagic.

The serum amylase, moreover, almost doubles.

These effects are blocked in a dose-dependent manner by the compounds ofthe invention. For example, compound 19 inhibits the weight increase ofthe pancreas and the serum amylase increase by 50% at a dose ofapproximately 1.5 mg/kg i.p.

The experimental data shown above have thus demonstrated the possibleutility of these compounds in the treatment of various pathologicalconditions concerning the gastrointestinal tract, for example in spasticsyndromes and pains generally, such as biliary diskinesia, or forencouraging emptying of the stomach and thus encouraging digestion.

These products could be used to particular advantage for the treatmentof pancreatitis, as safely active drugs whose efficacy has been shown bypertinent pharmacological experiment are lacking for this pathologicalcondition.

A favourable therapeutic use of many of the subject compounds canfurthermore be envisaged in various forms of anorexia and also in thetreatment of some pathological conditions of the CNS linked todeficiencies in the physiological neuron levels of CCK or otherbioactive peptides.

What is claimed is:
 1. Pharmaceutically active compounds of5-pentylamino-5-oxopentanoic and 4-pentylamino-4-oxobutanoic acidshaving the formula: ##STR11## in which n is selected from 1 and 2, R₁ oris 2-quinolinyl 3-quinolinyl, and R₂ is selected from the pentyl groupand alkoxyalkyl groups having 4 or 5 carbon atoms, or apharmaceutically-acceptable salt thereof.
 2. A compound of claim 1,wherein R₂ is selected from the pentyl and 3-methoxypropyl groups.
 3. Apharmaceutical preparation comprising a compound of claim 1 in an amounteffective as an antispastic and an inert carrier.
 4. A pharmaceuticalpreparation comprising a compound of claim 1 in an amount effective forthe treatment of pancreatitis, and an inert carrier.
 5. A pharmaceuticalpreparation comprising a compound of claim 1 in an amount effective forthe treatment of pathological conditions of the CNS linked todeficiencies in the physiological neuron levels of cholecystokinin orother bioactive polypeptides, and an inert carrier.
 6. A method for thetreatment of spastic conditions, pancreatitis, pathological conditionsof the CNS linked to deficiencies in the physiological neuron levels ofcholecystokinin or other bio-active polypeptides in the human or animalbody, the method comprising administering to said body an effectiveamount of a compound of claim 1.